Processes and intermediates for preparing steric compounds

ABSTRACT

This invention relates to processes and intermediates for the preparation of an alpha-amino beta-hydroxy acid of Formula 1  
                 
 
wherein the variables R 1 , R′ 1  and R 2  are defined herein and the compound of Formula 1 has an enantiomeric excess (ee) of 55% or greater.

CROSS-REFERENCE

This application claims the benefits of U.S. Provisional ApplicationSer. No. 60/782,976, filed Mar. 16, 2006, and U.S. ProvisionalApplication Ser. No. 60/844,771, filed Sep. 15, 2006.

FIELD OF THE INVENTION

This invention relates to processes and intermediates for thepreparation of protease inhibitors, in particular, serine proteaseinhibitors.

BACKGROUND OF THE INVENTION

Infection by hepatitis C virus (“HCV”) is a compelling human medicalproblem. HCV is recognized as the causative agent for most cases ofnon-A, non-B hepatitis, with an estimated human sero-prevalence of 3%globally [A. Alberti et al., “Natural History of Hepatitis C,” J.Hepatology, 31, (Suppl. 1), pp. 17-24 (1999)]. Nearly four millionindividuals may be infected in the United States alone. [M. J. Alter etal., “The Epidemiology of Viral Hepatitis in the United States,Gastroenterol. Clin. North Am., 23, pp. 437-455 (1994); M. J. Alter“Hepatitis C Virus Infection in the United States,” J. Hepatology, 31,(Suppl. 1), pp. 88-91 (1999)].

Upon first exposure to HCV, only about 20% of infected individualsdevelop acute clinical hepatitis while others appear to resolve theinfection spontaneously. In almost 70% of instances, however, the virusestablishes a chronic infection that may persist for decades. [S.Iwarson, “The Natural Course of Chronic Hepatitis,” FEMS MicrobiologyReviews, 14, pp. 201-204 (1994); D. Lavanchy, “Global Surveillance andControl of Hepatitis C,” J. Viral Hepatitis, 6, pp. 35-47 (1999)].Prolonged chronic infection can result in recurrent and progressivelyworsening liver inflammation, which often leads to more severe diseasestates such as cirrhosis and hepatocellular carcinoma. [M. C. Kew,“Hepatitis C and Hepatocellular Carcinoma”, FEMS Microbiology Reviews,14, pp. 211-220 (1994); I. Saito et. al., “Hepatitis C Virus Infectionis Associated with the Development of Hepatocellular Carcinoma,” Proc.Natl. Acad. Sci. USA, 87, pp. 6547-6549 (1990)]. Unfortunately, thereare no broadly effective treatments for the debilitating progression ofchronic HCV.

Compounds described as protease inhibitors, and in particular serineprotease inhibitors, useful in the treatment of HCV infections aredisclosed in WO 02/18369. Also disclosed therein are processes andintermediates for the preparation of these compounds. There remainshowever, a need for economical processes for the preparation of thesecompounds.

SUMMARY OF THE INVENTION

This invention relates to processes and intermediates for thepreparation of an alpha-amino beta-hydroxy acid of Formula 1

wherein the variables R₁, R′₁ and R₂ are defined herein and the compoundof Formula 1 has an enantiomeric excess (ee) of 55% or greater.

The process comprises the steps of oxidizing an unsaturated amide orester to form the corresponding epoxide, forming an alpha-hydroxy,beta-amino acid with an appropriate aminating reagent and resolving theamino-alcohol amide.

The processes and intermediates are particularly directed to thepreparation of (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide.

These processes and intermediates are useful for the preparation of aprotease inhibitor of Formula 2, wherein the variables R₃ and R₄ aredefined herein.

In one aspect, the invention features processes and intermediates usedin the preparation of the serine protease inhibitor of Formula 3.

DETAILED DESCRIPTION OF THE INVENTION I. Definitions

As used herein, the term “enantimoeric excess (ee) of 55% or greater”means that one enantiomer is present 55% or more than the other in achemical substance. The enantiomer can be a result of either the carboncenter to which the amino group is bonded (shown with an asterisk) inFormula 1

or the carbon center to which the hydroxyl group is bonded (also shownwith an asterisk) in Formula 1, or both carbon centers. For instance,numbered away from the carbonyl group, the compound can be (2S,3S),(2S,3R), (2R, 3R) or (2R, 3S) in these two carbon centers.

As used herein, “organic bases” that may be used in a process of thisinvention include tertiary organic bases that include, but are notlimited to trialkylamines, e.g. diethylisopropylamine, triethylamine,N-methylmorpholine and the like, and heteroaryl amines, e.g. pyridine,quinoline, and the like.

As used herein, the term “aliphatic” encompasses alkyl, alkenyl, andalkynyl.

As used herein, an “alkyl” group refers to a saturated aliphatichydrocarbon group containing 1-8 (e.g., 1-6 or 1-4) carbon atoms. Analkyl group can be straight or branched. Examples of an alkyl groupinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, and2-ethylhexyl. An alkyl group can be optionally substituted with one ormore substituents such as cycloalkyl, heterocycloalkyl, aryl,heteroaryl, alkoxy (two alkoxy groups on the same atom or adjacent atomsmay form a ring together with the atom(s) to which they are bound),aroyl, heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, acyl, sulfonyl(such as alkylsulfonyl or arylsulfonyl), sulfinyl (such asalkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy, urea,thiourea, sulfamoyl, sulfamide, oxo, carbamoyl.cycloalkyloxy,heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroarylalkoxy, amino, nitro, carboxy, cyano, oxo, halo, hydroxy,sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, alkylsulfonyl,aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino,heterocycloalkyl-carbonylamino, heterocycloalkyl-alkylcarbonylamino,heteroarylcarbonylamino, or heteroaralkylcarbonylamino.

As used herein, an “alkenyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and at least onedouble bond. Like an alkyl group, an alkenyl group can be straight orbranched. Examples of an alkenyl group include, but are not limited to,allyl, isoprenyl, 2-butenyl, and 2-hexenyl. An alkenyl group can beoptionally substituted with one or more substituents such as cycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkoxy (two alkoxy groups on thesame atom or adjacent atoms may form a ring together with the atom(s) towhich they are bound), aroyl, heteroaroyl, alkoxycarbonyl,alkylcarbonyloxy, acyl, sulfonyl (such as alkylsulfonyl orarylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such asalkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo,carbamoyl.cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy,aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy, cyano, oxo, halo,hydroxy, sulfo, mercapto, alkylsulfanyl, alkylsulfinyl, aminocarbonyl,alkylcarbonylamino, cycloalkylcarbonylamino,cycloalkyl-alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino,heterocycloalkyl-carbonylamino, heterocycloalkyl-alkylcarbonylamino,heteroarylcarbonylamino, or heteroaralkylcarbonylamino.

As used herein, an “alkynyl” group refers to an aliphatic carbon groupthat contains 2-8 (e.g., 2-6 or 2-4) carbon atoms and has at least onetriple bond. An alkynyl group can be straight or branched. Examples ofan alkynyl group include, but are not limited to, propargyl and butynyl.An alkynyl group can be optionally substituted with one or moresubstituents such as cycloalkyl, heterocycloalkyl, aryl, heteroaryl,alkoxy (two alkoxy groups on the same atom or adjacent atoms may form aring together with the atom(s) to which they are bound), aroyl,heteroaroyl, alkoxycarbonyl, alkylcarbonyloxy, acyl, sulfonyl (such asalkylsulfonyl or arylsulfonyl), sulfinyl (such as alkylsulfinyl),sulfanyl (such as alkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl,sulfamide, oxo, carbamoyl, cycloalkyloxy, heterocycloalkyloxy, aryloxy,heteroaryloxy, aralkyloxy, heteroarylalkoxy, amino, nitro, carboxy,cyano, oxo, halo, hydroxy, sulfo, mercapto, alkylsulfanyl,alkylsulfinyl, alkylsulfonyl, aminocarbonyl, alkylcarbonylamino,cycloalkylcarbonylamino, cycloalkyl-alkylcarbonylamino,arylcarbonylamino, aralkylcarbonylamino, heterocycloalkyl-carbonylamino,heterocycloalkyl-alkylcarbonylamino, heteroarylcarbonylamino, orheteroaralkylcarbonylamino.

As used herein, an “amino” group refers to —NRXRY wherein each of RX andRY is independently hydrogen, alkyl, cycloalkyl, (cycloalkyl)alkyl,aryl, aralkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, heteroaryl, orheteroaralkyl each of which are defined herein and are optionallysubstituted. When the term “amino” is not the terminal group (e.g.,alkylcarbonylamino), it is represented by —NRX—. RX has the same meaningas defined above.

As used herein, an “aryl” group used alone or as part of a larger moietyas in “aralkyl”, “aralkoxy”, or “aryloxyalkyl” refers to phenyl,naphthyl, or a benzofused group having 2 to 3 rings. For example, abenzofused group includes phenyl fused with one or two C4-8 carbocyclicmoieties, e.g., 1, 2, 3, 4-tetrahydronaphthyl, indanyl, or fluorenyl. Anaryl is optionally substituted with one or more substituents such asalkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such astrifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy,cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy,alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino,cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino,arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxy, acyl, mercapto, sulfonyl (such as alkylsulfonyl), sulfinyl(such as alkylsulfinyl), sulfanyl (such as alkylsulfanyl), sulfoxy,urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

As used herein, an “aralkyl” group refers to an alkyl group (e.g., aC₁₋₄ alkyl group) that is substituted with an aryl group. Both “alkyl”and “aryl” are defined herein. An example of an aralkyl group is benzyl.An “heteroaralkyl” group refers to an alkyl group that is substitutedwith a heteroaryl. Both “alkyl” and “heteroaryl” are defined herein. Asused herein, a “cyclcoaliphatic” group encompasses a “cycloalkyl” groupand a “cycloalkenyl” group.

As used herein, a “cycloalkyl” group refers to a saturated carbocyclicmono- or bicyclic (fused or bridged) ring of 3-10 (e.g., 5-10) carbonatoms. Examples of cycloalkyl groups include cyclopropyl, cyclopentyl,cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl,decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl,bicyclo[3.3.1]nonyl, and bicyclo[3.3.2.]decyl, and adamantyl. A“cycloalkenyl” group, as used herein, refers to a non-aromaticcarbocyclic ring of 3-10 (e.g., 4-8) carbon atoms having one or moredouble bond. Examples of cycloalkenyl groups include cyclopentenyl,1,4-cyclohexa-di-enyl, cycloheptenyl, cyclooctenyl, hexahydro-indenyl,octahydro-naphthyl, bicyclo[2.2.2]octenyl, and bicyclo[3.3.1]nonenyl. Acycloalkyl or cycloalkenyl group can be optionally substituted with oneor more substituents such as alkyl (including carboxyalkyl,hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl,cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl,(heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy, cycloalkyloxy,heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy,alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino,cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino,arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxy, acyl, mercapto, sulfonyl (such as alkylsulfonyl orarylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such asalkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, orcarbamoyl.

As used herein, the term heterocycloaliphatic encompasses aheterocycloalkyl group and a heterocycloalkenyl group.

As used herein, a “heterocycloalkyl” group refers to a 3- to 10-memberedmono- or bicylic (fused or bridged) (e.g., 5- to 10-membered mono- orbicyclic) saturated ring structure, in which one or more of the ringatoms is a heteroatom, e.g., N, O, or S. Examples of a heterocycloalkylgroup include piperidinyl, piperazinyl, tetrahydropyranyl,tetrahydrofuryl, dioxolanyl, oxazolidinyl, isooxazolidinyl, morpholinyl,octahydro-benzofuryl, octahydro-chromenyl, octahydro-thiochromenyl,octahydro-indolyl, octahydro-pyrindinyl, decahydro-quinolinyl,octahydro-benzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl,1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, anad2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. A monocyclic heterocycloalkyl groupmay be fused with a phenyl moiety such as tetrahydroisoquinoline. A“heterocycloalkenyl” group, as used herein, refers to a mono- or bicylic(e.g., 5- to 10-membered mono- or bicyclic) non-aromatic ring structurehaving one or more double bonds, and wherein one or more of the ringatoms is a heteroatom, e.g., N, O, or S. A heterocycloalkyl orheterocycloalkenyl group can be optionally substituted with one or moresubstituents such as alkyl (including carboxyalkyl, hydroxyalkyl, andhaloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl,(cycloalkyl)alkyl, heterocycloalkyl (such as a benzimidazolidinyl),(heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy (two alkoxy groups onthe same atom or adjacent atoms may form a ring together with theatom(s) to which they are bound), cycloalkyloxy, heterocycloalkyloxy,aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl,heteroaroyl, amino, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy,aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino,(cycloalkyl)alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxy, acyl, mercapto, sulfonyl (such as alkylsulfonyl orarylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such asalkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, orcarbamoyl.

A “heteroaryl” group, as used herein, refers to a monocyclic, bicyclic,or tricyclic ring structure having 4 to 15 ring atoms wherein one ormore of the ring atoms is a heteroatom, e.g., N, O, or S and wherein oneor more rings of the bicyclic or tricyclic ring structure is aromatic. Aheteroaryl group includes a benzofused ring system having 2 to 3 rings.For example, a benzofused group includes phenyl fused with one or twoC₄₋₈ heterocyclic moieties, e.g., indolinyl and tertahydroquinolinyl.Some examples of heteroaryl are azetidinyl, pyridyl, furyl, pyrrolyl,thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, tetrazolyl,benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene,phenothiazine, dihydroindole, and benzo[1,3]dioxole. A heteroaryl isoptionally substituted with one or more substituents such as alkyl(including carboxyalkyl, hydroxyalkyl, and haloalkyl such astrifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, alkoxy,cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy,heteroaralkyloxy, aroyl, heteroaroyl, amino, nitro, carboxy,alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino,cycloalkylcarbonylamino, (cycloalkyl)alkylcarbonylamino,arylcarbonylamino, aralkylcarbonylamino,(heterocycloalkyl)carbonylamino, (heterocycloalkyl)alkylcarbonylamino,heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo,hydroxy, acyl, mercapto, sulfonyl (such as alkylsulfonyl orarylsulfonyl), sulfinyl (such as alkylsulfinyl), sulfanyl (such asalkylsulfanyl), sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, orcarbamoyl. A “heteroaralkyl” group, as used herein, refers to an alkylgroup (e.g., a C₁₋₄ alkyl group) that is substituted with a heteroarylgroup. Both “alkyl” and “heteroaryl” have been defined above.

As used herein, “cyclic moiety” includes cycloalkyl, heterocycloalkyl,cycloalkenyl, heterocycloalkenyl, aryl, or heteroaryl, each of which hasbeen defined previously.

As used herein, an “acyl” group refers to a formyl group or alkyl-C(═O)—where “alkyl” has been defined previously. Acetyl and pivaloyl areexamples of acyl groups.

As used herein, a “carbamoyl” group refers to a group having thestructure —O—CO—NRxRy or —NRx—CO—O-Rz wherein Rx and Ry have beendefined above and Rz can be alkyl, aryl, aralkyl, heterocycloalkyl,heteroaryl, or heteroaralkyl.

As used herein, a “carboxy” and a “sulfo” group refer to —COOH or—COOR_(X) and —SO₃H or —SO₃R_(X), respectively.

As used herein, an “alkoxy” group refers to an alkyl-O— group where“alkyl” has been defined previously.

As used herein, a “sulfoxy” group refers to —O—SO—R_(X) or —SO—O—R_(X),where R_(X) has been defined above.

As used herein, a “sulfonyl” group refers to —S(O)₂—R_(X), wherein R_(X)has been defined above.

As used herein a “sulfinyl” group refers to —S(O)—R_(X), wherein R_(X)has been defined above.

As used herein a “sulfanyl” group refers to —S—R_(X), wherein R_(X) hasbeen defined above.

As used herein, a “halogen” or “halo” group refers to fluorine,chlorine, bromine or iodine.

As used herein, a “haloaliphatic” group refers to an aliphatic groupsubstituted with 1-3 halogen. For instance, the term haloalkyl includesthe group —CF₃.

As used herein, a “sulfamoyl” group refers to the structure—S(O)₂—NR_(x)R_(y) or —NR_(x), —S(O)₂—Rz wherein Rx, Ry, and Rz havebeen defined above.

As used herein, a “sulfamide” group refers to the structure—NR_(X)—S(O)₂—NR_(Y)R_(Z) wherein R_(X), R_(Y), and R_(Z) have beendefined above.

As used herein, a “carbonylamino” group used alone or in connection withanother group refers to an amido group such as —C(O)—NR_(X)—,—NR_(X)—C(O)—, and —C(O)—N(R_(X))₂. For instance an alkylcarbonylaminoincludes alkyl-C(O)—NR_(X)— and alkyl-NR_(X)—C(O)—.

As used herein, a “urea” group refers to the structure—NR_(X)—CO—NR_(Y)R_(Z) and a “thiourea” group refers to the structure—NR_(X)—CS—NR_(Y)R_(Z). R_(X), R_(Y), and R_(Z) have been defined above.

The phrase “optionally substituted” is used interchangeably with thephrase “substituted or unsubstituted.” As described herein, compounds ofthe invention may optionally be substituted with one or moresubstituents, such as are illustrated generally above, or as exemplifiedby particular classes, subclasses, and species of the invention. Asdescribed herein, the variables encompass specific groups, such as alkyland aryl. Unless otherwise noted, each of the specific groups for thevariables may be optionally substituted with one or more substituentsdescribed herein. Each substituent of a specific group is furtheroptionally substituted with one to three of halo, cyano, alkoxy,hydroxyl, nitro, haloalkyl, and alkyl. For instance, an alkyl group maybe substituted with alkylsulfanyl and the alkylsulfanyl may beoptionally substituted with one to three of halo, cyano, alkoxy,hydroxyl, nitro, haloalkyl, and alkyl. As an additional example, thecycloalkyl portion of a (cycloalkyl)carbonylamino may be optionallysubstituted with one to three of halo, cyano, alkoxy, hydroxyl, nitro,haloalkyl, and alkyl.

In general, the term “substituted,” whether preceded by the term“optionally” or not, refers to the replacement of hydrogen radicals in agiven structure with the radical of a specified substituent. Specificsubstituents are described above in the definitions and below in thedescription of compounds and examples thereof. Unless otherwiseindicated, an optionally substituted group may have a substituent ateach substitutable position of the group, and when more than oneposition in any given structure may be substituted with more than onesubstituent selected from a specified group, the substituent may beeither the same or different at every position. A ring substituent, suchas a heterocycloalkyl, may be bound to another ring, such as acycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings shareone common atom. As one of ordinary skill in the art will recognize,combinations of substituents envisioned by this invention are thosecombinations that result in the formation of stable or chemicallyfeasible compounds.

The phrase “stable or chemically feasible,” as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

As used herein, the term “bicyclic fused ring system” or “bicyclic ringsystem” refers to two rings which share two atoms. Either ring may besaturated, partially unsaturated, or aromatic. Each ring also maycontain 1 to 3 heteroatoms.

As used herein, the term “tricyclic fused ring system” or “tricyclicring system” refers to a bicyclic ring system in which a third ring isfused to the bicyclic ring system such that the third ring shares atleast two atoms with the bicyclic ring system. In some embodiments, allthree rings share at least one common atom. Any of the rings in thetricyclic ring system may be saturated, partially unsaturated, oraromatic. Each of the rings may include 1 to 3 heteroatoms.

In some embodiments, aliphatic groups, alkyl groups, aryl groups,heterocyclic groups, carbocyclic groups, and bicyclic or tricyclic ringsystems contain one or more substituents. The substituents are selectedfrom those that will be stable under the reaction conditions of thepresent process, as would be generally known to those skilled in theart. Examples of substituents include halogen, -Q₁, —OQ₁, —OH, protectedOH (such as acyloxy), phenyl (Ph), substituted Ph, —OPh, substituted—OPh, —NO₂, —CN, —NHQ₁, —N(Q₁)₂, —NHCOQ₁, —NHCONHQ₁, —NQ₁CONHQ₁,—NHCON(Q₁)₂, —NQ₁CON(Q₁)₂, —NQ₁COQ₁, —NHCO₂Q₁, —NQ₁CO₂Q₁, —CO₂Q₁, —COQ₁,—CONHQ₁, —CON(Q₁)₂, —S(O)₂Q₁, —SONH₂, —S(O)Q₁, —SO₂NHQ₁, —SO₂N(Q₁)₂,—NHS(O)₂Q₁, —NQ₁S(O)₂Q₁, ═O, ═S, ═NNHQ₁, ═NN(Q₁)₂, ═N-OQ₁, ═NNHCOQ₁,═NNQ₁COQ₁, ═NNHCO₂Q₁, ═NNQ₁CO₂Q₁, ═NNHSO₂Q₁, ═NNQ₁SO₂Q₁, or ═NQ₁ whereQ₁ is an optionally substituted aliphatic, aryl or aralkyl group.

As used herein, nitrogen atoms on a heterocyclic ring may be optionallysubstituted. Suitable substituents on the nitrogen atom include Q₂,COQ₂, S(O)₂Q₂, and CO₂Q₂, where Q₂ is an aliphatic group or asubstituted aliphatic group.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

The term “substantially pure” refers to the stereochemical purity of acompound that is greater than 90%. In some embodiments, thestereochemical purity of a compound is greater than 95%. And in stillothers, the stereochemical purity of a compound is 99% or greater.

The term “selective crystallization” means crystallization of asubstantially pure isomer from a solvent containing a mixture ofisomers.

The term “dynamic crystallization” means crystallization of asubstantially pure isomer from a solvent containing a mixture of isomersunder conditions which cause isomerization of the mixture of isomers toan isomer which selectively crystallizes. For example, in the case ofresolving enantiomers, isomerization of the more soluble enantiomer tothe less soluble isomer results in crystallization of the less solubleisomer as the equilibrium between the isomers is driven bycrystallization toward the less soluble enantiomer. A specific exampleof dynamic crystallization may include the epimerization of an anomericcarbon in a solvent under conditions which selectively crystallizes onesubstantially pure enantiomer.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms.

Various “protecting groups,” “capping groups,” or “amine capping groups”may be used in the methods of this invention. Examples of amine cappinggroups or protecting groups include, but are not limited to, -Q⁷,—C(S)Q⁷, —C(O)OQ⁷, —SOQ⁷, —SO₂Q⁷, —SO₃Q⁷, —SO₂N(Q⁷)₂, —C(O)C(O)Q⁷,—C(O)C(O)OQ⁷, —C(O)CH₂C(O)Q⁷, —C(O)N(Q⁷)₂, —(CH₂)₀₋₂NHC(O)Q⁷,—C(═NH)N(Q⁷)₂, —C(O)N(OQ⁷)Q⁷, —C(═NOQ⁷)Q⁷, —P(O)(Q⁷)₂, and —P(O)(OQ⁷)₂;wherein Q⁷ is hydrogen, an optionally substituted aliphatic group, anoptionally substituted aryl group, or an optionally substitutedheterocyclic group. Preferably, Q⁷ is C₁₋₁₂ aliphatic, C₃₋₁₀cycloaliphatic, (C₃₋₁₀ cycloaliphatic)-C₁₋₁₂ aliphatic, C₆₋₁₀ aryl,(C₆₋₁₀ aryl)-(C₁₋₁₂ aliphatic)-, C₃₋₁₀ heterocyclyl, (C₆₋₁₀heterocyclyl)-C₁₋₁₂ aliphatic, C₅₋₁₀ heteroaryl, or (C₅₋₁₀heteroaryl)-(C₁₋₁₂ aliphatic)-.

As used herein, the term “lewis acid” refers to moiety capable ofsharing or accepting an electron pair. Examples of lewis acids include,but are not limited to, BF₃-etherates and metal halides, alkoxides, andmixed halide/alkoxides (e.g., Al(O-alkyl)₂Cl, Al(O-alkyl)Cl₂). Themetals can be aluminum, titanium, zirconium, magnesium, copper, zinc,iron, tin, boron, ytterbium, lanthanum, and samarium.

EDCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. HOBt is1-hydroxybenzotriazole. HOSuc is N-hydroxysuccinimide. THF istetrahydrofuran. TFA is trifluoroacetic acid. DCM is dichloromethane.DMAP is 4-dimethylaminopyridine. DIPEA is diisopropylethylamine. DMF isdimethylformamide. TFA is trifluoroacetic acid. CBZ isbenzyloxycarbonyl. ¹H NMR is proton nuclear magnetic resonance. TLC isthin layer chromatography. TEMPO is 2,2,6,6-Tetramethylpiperidinyloxyfree radical.

II. Processes and Intermediates

Generally, this invention relates to processes for and intermediatesused in the preparation of steric-specific compounds.

Specifically, the processes and intermediates described herein areuseful for the preparation of an HCV protease inhibitor of Formula 2.

wherein

R₃ is RW— or a P4-L3-P3-L2-P2-;

R₄ is —NH—CR₁R′₁—CH(OH)C(O)—NHR₂;

Each W is independently a bond, —NR₄, —O— or —S—;

Each of P2, P3 and P4 is independently a bond, H, an optionallysubstituted aliphatic, an optionally substituted heteroaliphatic, anoptionally substituted aryl, an optionally substituted heteroaryl, anoptionally substituted alkoxy, an optionally substituted alkylsufanyl,an optionally substituted aralkoxy, an optionally substitutedaralkylsulfanyl, an optionally substituted mono- or dialkylamino, anoptionally substituted mono- or diarylamino or an optionally substitutedmono- or diheteroarylamino, provided that when L2 is absent and P3 is H,that L3 and P4 are absent;

when P2 is not a terminal group, that P2 is bound to the core structureof formula 3 and P2 is also bound to L2, if present, or P3, if L2 isabsent;

when P3 is not a terminal group, that P3 is bound to L2, if present, orP2, if L2 is absent, and P3 is also bound to L3, if present, or P4, ifL3 is absent;

Each L2 or L3 is independently a bond, —C(O)— or —SO₂—;

Each R₁ and R′₁ is independently H, an optionally substituted aliphatic,an optionally substituted aryl, an optionally substituted aralkyl, anoptionally substituted heteroaliphatic or an optionally substitutedheteroaralkyl, or each R₁ and R′₁ together with the atom to which theyare attached may form a 3 to 7 membered optionally substitutedcycloaliphatic ring.

In some embodiments R₃ is P2-, which is represented by the structure:

wherein

Each T is independently a bond, H, —C(O)—, —O—C(O)—, —NHC(O)—,—C(O)C(O)— or —SO₂—;

Each R is independently H, an optionally substituted aliphatic, anoptionally substituted heteroaliphatic, an optionally substitutedcycloaliphatic, an optionally substituted heterocyclic, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, anoptionally substituted aryl or an optionally substituted heteroaryl; and

Each R₅ and R₆ is independently H, an optionally substituted aliphatic,an optionally substituted heteroaliphatic, an optionally substitutedheteroaryl, an optionally substituted phenyl, an optionally substitutedaralkyl or an optionally substituted heteroarylalkyl, or

R₅ and the adjacent R₆ taken together with the atoms to which they areattached form a 5- to 7-membered, optionally substituted monocyclicheterocycle, or a 6- to 12-membered, optionally substituted bicyclicheterocycle, in which each heterocycle ring optionally contains anadditional heteroatom selected from —O—, —S— or —NR₄—; and Each R₇ isindependently H, an optionally substituted aliphatic, an optionallysubstituted heteroaliphatic, an optionally substituted heteroaryl, or anoptionally substituted phenyl.

In some embodiments, R₁ is P3-L2-P2 which is represented by thestructure:

In some embodiments, R₃ is P4-L3-P3- L2-P2 which is represented by thestructure:

wherein

Each T is independently a bond, H, —C(O)—, —O—C(O)—, —NHC(O)—,—C(O)C(O)— or —SO₂—;

Each R is independently H, an optionally substituted aliphatic, anoptionally substituted heteroaliphatic, an optionally substitutedcycloaliphatic, an optionally substituted heterocyclic, an optionallysubstituted aralkyl, an optionally substituted heteroaralkyl, anoptionally substituted aryl or an optionally substituted heteroaryl;

Each R₅, R₆, R₇ and R₈ is independently H, an optionally substitutedaliphatic, an optionally substituted heteroaliphatic, an optionallysubstituted heteroaryl, an optionally substituted phenyl, an optionallysubstituted aralkyl or an optionally substituted heteroarylalkyl, or

R₅ and the adjacent R₆ taken together with the atoms to which they areattached form a 5 to 7 membered, optionally substituted monocyclicheterocycle, or a 6 to 12 membered, optionally substituted bicyclicheterocycle, in which each heterocycle ring optionally contains anadditional heteroatom selected from —O—, —S— or —NR₄—; and each R₇ isindependently H, an optionally substituted aliphatic, an optionallysubstituted heteroaliphatic, an optionally substituted heteroaryl, or anoptionally substituted phenyl;

R₇ and the adjacent R₆ together with the atoms to which they areattached may form a 5 to 7 membered, optionally substituted monocyclicheterocycle, a 5 to 7 membered, optionally substituted monocyclic aryl,a 6 to 12 membered, optionally substituted bicyclic heterocycle, or a 6to 12 membered, optionally substituted bicyclic aryl, in which eachheterocycle or aryl ring optionally contains an additional heteroatomselected from —O—, —S— or —NR₄—;

R₈ and the adjacent R₆ together with the atoms to which they areattached may form a 5 to 7 membered, optionally substituted monocyclicheterocycle, a 5 to 7 membered, optionally substituted monocyclicheteroaryl, a 6 to 12 membered, optionally substituted bicyclicheterocycle, or a 6 to 12 membered, optionally substituted bicyclicheteroaryl, in which each heterocycle or heteroaryl ring optionallycontains an additional heteroatom selected from —O—, —S— or —NR₄—;

R₈ and R together with the atoms to which they are attached may form a 5to 7 membered, optionally substituted monocyclic heterocycle, a 5 to 7membered, optionally substituted monocyclic aryl, a 6 to 12 membered,optionally substituted bicyclic heterocycle, or a 6 to 12 membered,optionally substituted bicyclic aryl, in which each heterocycle or arylring optionally contains an additional heteroatom selected from —O—, —S—or —NR₄—;

when R₅ and R₆ together with the atoms to which they are attached form aring, R₇ and the ring system formed by R₅ and R₆ may form an 8- to14-membered optionally substituted bicyclic fused ring system, whereinthe bicyclic fused ring system is optionally further fused with anoptionally substituted phenyl to form an optionally substituted 10- to16-membered tricyclic fused ring system.

An example of the HCV protease inhibitors of Formula 2 is the compoundof Formula 3 shown below.

In one aspect, the invention provides processes and intermediates forproducing an x-hydroxy-β-amino acid derivative of Formula 1, which isuseful in producing protease inhibitors:

wherein R₁ and R′₁ are each independently H, optionally substitutedaliphatic, optionally substituted cycloaliphatic, optionally substitutedarylaliphatic, optionally substituted heteroaliphatic or optionallysubstituted heteroarylaliphatic and R₂ is H, optionally substitutedaliphatic, optionally substituted cycloaliphatic, optionally substitutedarylaliphatic, optionally substituted heteroaliphatic or optionallysubstituted heteroarylaliphatic and the amino-alcohol amide of Formula 1has an enantiomeric excess (ee) of greater than 55% (for the definitionof ee see, e.g., Jerry March, Advanced Organic Chemistry, John Wiley andSons, Inc., 1992, p. 125).

In one embodiment, the invention provides a process and intermediatesfor preparing a compound of Formula 1 as outlined in Scheme 1.

Referring to Scheme I, R₁ and R′₁ are as previously described; R′₂ is—NHR₂ or —OE wherein R₂ is as previously described and E is C₁-C₅ alkylor optionally substituted benzyl. The unsaturated compound i isconverted the epoxide ii (step a) using known methods, e.g., oxidationwith a peracid such as, for example, meta-chlorperbenzoic acid orperacetic acid (see, e.g., R. S. Porto, M. L. A. A. Vasconcellos, E.Ventura, F. Coelho, Synthesis, 2005, 2297-2306), hydrogen peroxide (see,e.g., Dorothee Felix, Claude Wintner, and A. Eschenmoser, OrganicSynthesis, Collective Volume 6, p. 679), urea-hydrogen peroxide (alsocalled urea hydroperoxide) in the presence of trifluoroacetic anhydride,Oxone® (KHSO₅, potassium peroxomonosulfate) or an organic peroxide suchas, for example, tert-butyl hydroperoxide. Alternatively, the epoxide iimay be obtained by using a glycidic ester condensation (see, e.g., M.Ballester, Chem. Revs. 55, 283-300 (1955); D. M. Burness, OrganicSynthesis, Collective Volume 4, p. 649).

In some embodiments, the epoxidation may be performed to provideoptically enriched epoxides (see, e.g., H. Kakei, R. Tsuji, T. Ohshima,M. Shibasaki, J. Am. Chem. Soc., 2005, 127, 8962-8963; M. Marigo, J.Franzen, T. B. Poulsen, W. Zhuang, K. A. Jorgensen, J. Am. Chem. Soc.,2005, 127, 6284-6289; M. Shibisaki, et. al., U.S. Pat. No. 6,833,442(BINOL Ars complex); R. Kino, K. Daikai, T. Kawanami, H. Furuno, J.Inanaga, Org. Biomol. Chem., 2004, 2, 1822-1824; Y. Shi, U.S. Pat. No.6,348,608 (OXONE, EDTA, optically active ketone))

The epoxidation step may be conducted on either an ester (R′₂=—OE) or onan amide (R′₂=—NHR₂). When the epoxidation step is performed on anester, the ester is subsequently converted to an amide. It is within thescope of the invention that formation of the amide can be performed atany stage of the process using known methods and protecting groups whereappropriate.

Reaction of the epoxide ii with a suitable amination reagent (step b)provides the amino alcohol 3. Suitable amination reagents are thosewhich may be converted to the amino compound III. Examples of suitableamination reagents include azide, phthalimide and an optionallysubstituted benzyl amine.

In step c, the mixture of amino alcohols of Formula iii is resolved toprovide the optically active compound of Formula iv. Suitable methodsfor resolving the mixture iii include, for example, formation of a saltwith a suitable optically active organic acid. Suitable optically activeorganic acids include, but are not limited to, tartaric acid, malicacid, di-isopropylidenegulonic acid and deoxycholic acid.

In one embodiment, R′₂ of Formula i is —NHR₂

In one embodiment, the epoxidation of i is performed using tert-butylhydroperoxide in the presence of a base such as, for example, sodiumhydroxide or butyl lithium.

In another embodiment, the epoxidation is performed using potassiummonopersulfate, ethylenediamine tetraacetic acid and an optionallyoptically active ketone.

In one embodiment, the amino-alcohol of Formula iii has a transconfiguration.

In one embodiment, the compound of Formula iv has a 2-(S), 3(S)configuration.

In one embodiment, the amination of ii to give the amino alcohol iii isperformed by reaction of ii with sodium azide followed by reduction ofthe intermediate azide with hydrogen in the presence of a palladium oncarbon catalyst.

In another embodiment, the resolution of iii to iv is performed byforming a salt with an optically active acid and crystallizing the thusobtained salt.

In another embodiment, the optically active organic acid is tartaricacid.

In a further embodiment, the optically active organic acid isdeoxycholic acid.

In one embodiment, R₁ is C₁-C₆ alkyl and R′₁ is H.

In another embodiment, R₂ is C₁-C₆ alkyl or C₁-C₆ cycloalkyl.

In another embodiment, R₂ is cyclopropyl.

In another embodiment, the amino-hydroxy compounds of formula iii may beprepared according to methods described in U.S. Pat. Nos. 6,020,518,6,087,530 and 6,639,094, each of which is incorporated herein in itsentirety by reference.

In another embodiment, as illustrated in Scheme II, this inventionprovides a process and intermediates for preparing a compound of Formula3.

In Scheme II, the bicyclic amino ester of formula 1a is reacted with aprotected amino acid of Formula 5, wherein Z is an amine protectinggroup which can be removed under acidic, basic or hydrogenatingconditions different from those used for removing an R₁ protectinggroup, in the presence of a coupling reagent to give an amide-ester ofFormula 6. The protecting group Z is removed from the amide-ester ofFormula 6 to give the amine-ester compound of Formula 7.

Reacting the amino compound of Formula 7 with the protected amino acid 8in the presence of a coupling reagent gives the tripeptide of Formula 9.

Removing the protecting group Z in the tripeptide of Formula 9 providesthe free amino-tripeptide of Formula 10.

Reacting the amino-tripeptide of Formula 10 with pyrazine-2-carboxylicacid in the presence of a coupling reagent yields the amide-tripeptideester of Formula 11.

Hydrolysis of the ester of the amide-tripeptide ester of Formula 11provides the amide-tripeptide acid of Formula 12.

Reacting the amide-tripeptide acid of Formula 12 with the amino-hydroxyamide of Formula 20 in the presence of a coupling reagent gives thehydroxy-peptide of Formula 13.

In the final step, oxidation of the hydroxy group of Formula 12 providesthe compound of Formula 3.

Any of the intermediates obtained as described herein, may be used withor without isolation from the reaction mixture. The desired proteaseinhibitor may be derived by attaching the appropriate P₂, P₂—P₃, orP₂—P₃—P₄ moiety. A coupling of an amine with such a moiety may becarried out using the corresponding carboxylic acid, or reactiveequivalent thereof, under standard amide bond-forming or couplingconditions. A typical coupling reaction includes a suitable solvent, theamine in a concentration ranging from about 0.01 to 10 M, preferablyabout 0.1 to 1.0 M, the requisite carboxylic acid, a base and a peptidecoupling reagent.

If an amine is used without isolation, the coupling may be carried outin situ in the solvent of the reaction mixture used in the preparationof the amine, or in a different solvent. To this reaction mixture, therequisite carboxylic acid may be added and the reaction maintained at atemperature in the range of about 0 to 100° C., preferably between about20 to about 40° C. The base and peptide coupling reagent are then addedto the mixture, which is maintained at a temperature in the range offrom about 0 to about 60° C., preferably between about 20 to about 40°C. The base is typically a tertiary amine base, such as triethylamine,diisopropylethylamine, N-methylmorpholine, DBU, DBN, N-methylimidazole,preferably triethylamine or diisopropylethylamine. The amount of baseused is generally up to about 20 equivalents per equivalent of theamine, preferably at least about 3 equivalents of base. Examples ofpeptide coupling reagents include DCC (dicyclohexylcarbodiimide), DIC(diisopropylcarbodiimide), di-p-toluoylcarbodiimide, BDP(1-benzotriazolediethylphosphate-1-cyclohexyl-3-(2-morpholinylethyl)carbodiimide), EDC(1-(3-dimethylaminopropyl-3-ethyl-carbodiimide hydrochloride), cyanuricfluoride, cyanuric chloride, TFFH (tetramethyl fluoroformamidiniumhexafluorophosphosphate), DPPA (diphenylphosphorazidate), BOP(benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate), HBTU(O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate),TBTU (O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate), TSTU(O—(N-succinimidyl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate),HATU(N—[(dimethylamino)-1-H-1,2,3-triazolo[4,5,6]-pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide), BOP—Cl(bis(2-oxo-3-oxazolidinyl)phosphinic chloride), PyBOP((1-H-1,2,3-benzotriazol-1-yloxy)-tris(pyrrolidino)phosphoniumtetrafluorophopsphate), BrOP (bromotris(dimethylamino)phosphoniumhexafluorophosphate), DEPBT(3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one) PyBrOP(bromotris(pyrrolidino)phosphonium hexafluorophosphate). EDC, HOAT,BOP—Cl and PyBrOP are preferred peptide coupling reagents. The amount ofpeptide coupling reagent is in the range of about 1.0 to about 10.0equivalents. Optional reagents that may be used in the amidebond-forming reaction include DMAP (4-dimethylaminopyridine) or activeester reagents, such as HOBT (1-hydroxybenzotriazole), HOAT(hydroxyazabenzotriazole), HOSu (hydroxysuccinimide), HONB(endo-N-hydroxy-5-norbornene-2,3-dicarboxamide), in amounts ranging fromabout 1.0 to about 10.0 equivalents.

Alternatively, one may treat an amine with a reactive equivalent of theR₁ carboxylic acid, such as P₂—, P₃—P₂—, or P₄—P₃—P₂—C(═O)X¹, where—C(═O)X¹ is a group that is more reactive than COOH in the couplingreaction. Examples of —C(═O)X¹ groups include groups where X¹ is Cl, F,OC(═O)R(R=aliphatic or aryl), —SH, —SR, —SAr, or —SeAr.

Acid and amine protecting groups as used herein are known in the art(see, e.g., T. W. Greene & P. G. M Wutz, Protective Groups in OrganicSynthesis, 3^(rd) Edition, John Wiley & Sons, Inc. (1999) and theearlier editions of this book).

A number of chemical groups are known that may be used as the P₃—P₂—portion of the protease inhibitor. Examples of such P₃—P₂— groups areincluded in U.S. Application No. 60/709,964, which is also incorporatedhereto by reference in its entirety.

Other methods well known in the art may also be used to implement themethods of this invention and even to make the compounds of thisinvention. See, e.g., WO 07/022,459 A2, which is incorporated herein byreference in its entirety.

III Examples

The following examples are for the purpose of illustration only and arenot to be construed as limiting the scope of the invention in any way.

Example 1 3-Propyloxirane-2-carboxylic acid

A flask equipped with an overhead stirrer, thermometer and additionfunnel was placed under a nitrogen atmosphere then charged withtrans-2-hexenoic acid (69.8 g, 611 mmol), water (420 mL) and acetone(420 mL). Sodium bicarbonate (NaHCO₃, 224 g, 2.66 mol) was then addedportion-wise keeping the reaction temperature at 25±5° C. Once all ofthe sodium bicarbonate had been added, a solution of OXONE® (454 g, 738mmol) in 4×10⁻⁴ M ethylenediaminetetraacetic acid disodium saltdehydrate (Na₂EDTA; 1.32 L) was charged to the addition funnel and addedover 90 minutes keeping the reaction temperature at 25±5° C. and the pHbetween 9.5 and 7.5. The reaction mixture was then allowed to stir for16 h, after which time no (E)-hex-2-enoic acid was observed by HPLCanalysis. The mixture was cooled to 0±5° C., acidified to pH 2 with 6 NHCl (515 mL, 2.8 mol) and extracted with ethyl acetate (EtOAc; 3×250mL). The combined organic phases were dried over sodium sulfate(Na₂SO₄), filtered then concentrated under reduced pressure to providethe title compound (60.4 g, 76%) as a yellow oil.

¹H NMR (500 MHz, d₆-DMSO) δ12.88 (br s, 1H), 3.21 (s, 1H), 3.06-3.03 (m,1H), 1.58-1.36 (m, 4H), 0.91 (t, J=7.5 Hz, 3H).

Example 2 N-cyclopropyl-3-propyloxirane-2-carboxamide

A flask equipped with an overhead stirrer, thermometer and additionfunnel was placed under a nitrogen atmosphere then charged with the acidof Example 1 (20.0 g, 154 mmol), and isopropyl acetate (IPAc; 200 mL)then cooled to 0±5° C. 4-Methylmorpholine (NMM, 154 mL, 17 mL) wascharged to the addition funnel then added maintaining the temperature at0±5° C. Once addition was complete the addition funnel washed with IPAc(10 mL) and then charged with isobutyl chloroformate (IBCF, 137 mmol,19.5 mL) which was added keeping the temperature at 0±5° C. The reactionmixture was stirred at 0±5° C. for 90 min after which time a solution ofcyclopropylamine (154 mmol, 10.7) in IPAc (80 mL) was added keeping thetemperature at 0±5° C. Upon completion of addition the reaction waswarmed to 25±5° C. and allowed to stir for 18 h. Sodium hydroxide (231mL, 1.0 N) was added and the biphasic mixture stirred vigorously for 30min, then the layers were separated. The organic phase was then washedwith HCl (231 mL, 1.0 N). The combined organic phases were dried oversodium sulfate (Na₂SO₄), filtered and concentrated under reducedpressure to provide the title compound (19.5 g, 75%) as an orange oil.

¹H NMR (500 MHz, d₆-DMSO) 7.97 (bs, 1H), 3.10 (d, J=1.9 Hz, 1H),2.99-2.95 (m, 1H), 2.67-2.61 (m, 1H), 1.60-1.36 (m, 4H), 0.90 (t, J=7.3Hz, 3H), 0.62-0.58 (m, 2H), 0.47-0.43 (m, 2H)

Example 3 Alternate preparation ofN-cyclopropyl-3-propyloxirane-2-carboxamide

A flask equipped with a stir bar, thermometer and addition funnel wasplaced under a nitrogen atmosphere then charged with the acid of Example1 (5.0 g, 38 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (EDCI; 8.1 g, 42 mmol), 1-hydroxybenzotriazole hydrate(HOBt; 5.7 g, 42 mmol) and N,N-dimethylformamide (DMF; 50 mL) thencooled to 0±5° C. The addition funnel was charged with NMM (5.9 mL, 54mmol) which was then added to the reaction mixture maintaining thetemperature at 0±5° C. The mixture was stirred for 30 minutes thencyclopropylamine (2.9 mL, 42 mmol) was added and the reaction allowed towarm to 25±5° C. over 16 hours. Hydrochloric acid (50 mL, 1.0 N) andIPAc (50 mL) were added and then the mixture stirred for an additional30 minutes. The contents were transferred to separatory funnel, thelayers separated then the organic layer washed sequentially with HCl (50mL, 1.0 N), saturated aqueous NaHCO₃ (2×50 mL), and brine (2×50 mL). Thecombined organic phases were dried over sodium sulfate (Na₂SO₄),filtered then concentrated under reduced pressure to provide title amide(3.2 g, 50%) as an orange oil.

Example 4 Trans-N-cyclopropyl-2-hexenamide

A flask equipped with an overhead stirred, thermometer and additionfunnel was placed under a nitrogen atmosphere then charged with(E)-hex-2-enoic acid (89.8 g, 787 mmol), EDCI (158.3 g, 826 mmol), HOBt(112.0 g, 826 mmol) and IPAc (890 mL) then cooled to 0±5° C. Theaddition funnel was charged with NMM (99.1 mL, 1.6 mol) which was thenadded to the reaction mixture maintaining the temperature at 0±5° C. Themixture was stirred for 30 minutes then cyclopropylamine (60.0 mL, 866mmol) was added and the reaction allowed to warm to 25±5° C. over 16hours. The reaction mixture washed by adding hydrochloric acid (500 mL,1.0 N) and the mixture stirred vigorously for 30 minutes then allowed tosit for 30 minutes; the layers were separated and the washing procedurerepeated. Sodium hydroxide (500 mL, 1.0 N) was added and then themixture stirred vigorously for 30 minutes then allowed to sit for 30minutes; the layers were separated and base wash procedure repeated.Water (500 mL) was added and then the mixture stirred vigorously for 30minutes then allowed to sit for 30 minutes; the layers were separatedand the wash procedure repeated. The combined organic phases wereconcentrated under reduced pressure to ⅓ original volume then IPAc (600mL) was added; this was repeated two times when a white precipateformed. The slurry was then concentrated under atmospheric pressure to ⅔original volume then cooled to 50±5° C. N-heptane (890 mL) was slowlyadded while the reaction was cooled to −5±5° C. and held at thistemperature for 4 hours. The solid was filtered, washed with coldn-heptane (2×250 mL) and dried to provide the title amide (82.4 g, 68%)as a fine white solid.

¹H NMR (500 MHz, d₆-DMSO) 7.89 (s, 1H), 6.58 (dt, J=15.2, 7.0 Hz, 1H),5.80 (dt, J=15.2, 1.3 Hz, 1H), 2.70-2.65 (m, 1H), 2.12-2.06 (m, 2H),1.44-1.37 (m, 2H), 0.88 (t, J=7.3 Hz, 3H), 0.64-0.60 (m, 2H), 0.42-0.38(m, 2H).

Example 5 N-cyclopropyl-3-propyloxirane-2-carboxamide

A flask equipped with an overhead stirrer, thermometer and additionfunnel was placed under a nitrogen atmosphere then charged withtert-butyl hydrogen peroxide (TBHP; 95 mL, 5.5 M, 522 mmol) andtetrahydrofuran (THF; 200 mL). The reaction was cooled to −20±5° C. andn-butyl lithium (n-BuLi; 235 mL, 2.5 M, 587 mmol) was charged to theaddition funnel and slowly added, keeping the reaction temperature below−5±5° C. Upon completion of addition the reaction was warmed to 0±5° C.and the amide of Example 4 (19.80 g, 130 mmol) in THF (20 mL) was addedmaintaining the temperature at 0±5° C. after which the temperature wasincreased to 25±5° C. and the reaction stirred for 12 hours. After thistime IPAc (200 mL) and saturated aqueous sodium hydrosulfite (200 mL)were added and the reaction stirred for 60 min. The layers wereseparated and the aqueous layer extracted with IPAc (twice, 75 mL each).The combined organic phases were dried over sodium sulfate (Na₂SO₄),filtered and concentrated under reduced pressure to provide the titlecompound (21.87 g, 99%).

Example 6 N-cyclopropyl-3-propyloxirane-2-carboxamide

A flask equipped with a stir bar, thermometer and addition funnel wasplaced under a nitrogen atmosphere then charged with samarium (III)isopropoxide (Sm(O-i-Pr)₃, 430 mg, 1.3 mmol), triphenyl arsine oxide(Ph₃As=O; 420 mg, 1.3 mmol), S-(−)1,1′-bi-2-naphthol ((S)—BINOL), 370mg, 1.3 mmol), 4 Å molecular sieves (13 g) and THF (20 mL) then stirredfor 30 min at 25±5° C. Tert-butyl hydroperoxide (2.8 mL, 5.5 M, 16 mmol)was then added. The mixture stirred for 30 minutes at 25±5° C., theamide of Example 4 (2.0 g, 13 mmol) in THF (2.0 mL) was then added. Thereaction was stirred for 14 hours after which time the reaction hadreached 95% completion as determined by HPLC.

Example 7 N-cyclopropyl-3-propyloxirane-2-carboxamide

To a three-neck 250 mL round bottom flask equipped with mechanicalstirrer and containing (E)-N-cyclopropylhex-2-enamide (10.0 g, 65.3mmole) and urea hydrogen peroxide (UHP) (25.0 g, 4.0 eq.) in CH₂Cl₂ (100mL, 10 vol) at 0° C., was added trifluoroacetic anhydride (41.1 g, 27.2mL, 3.0 eq.). The reaction mixture was heated to 35±5° C. and stirredfor 2 hours. After cooling the reaction mixture down to roomtemperature, another aliquot of trifluoroacetic anhydride (13.7 g, 9.0mL, 1.0 eq.) was added. The reaction mixture was heated again to 35±5°C. and stirred for another 3 hours.

The reaction mixture was then again cooled to 0° C. and quenched byadding saturated NaHCO₃ (5 vol.) slowly and stirring for 30 minutes. Theorganic layer was separated, and the aqueous layer was extracted withCH₂Cl₂ (50 mL, 5 vol). The combined organic layer was dried andevaporated to afford 10.0 g (90%) of the crude the product,N-cyclopropyl-3-propyloxirane-2-carboxamide, as a pale yellow oil. Thecrude product was used for the next step without further purification.

Example 8 3-Azido-N-cyclopropyl-2-hydroxyhexanamide

A flask equipped with an overhead stirrer, thermometer and refluxcondenser was placed under a nitrogen atmosphere then charged with theepoxide of Example 5 (20.0 g, 118 mmol), sodium azide (NaN₃; 31.0 g, 473mmol), magnesium sulfate (MgSO₄; 14.0 g, 118 mmol) and methanol (MeOH;200 mL). The mixture was heated to 65±5° C. for 2 hours then cooled to25±5° C. and filtered through a pad of Celite 545. The solvent wasremoved under reduced pressure resulting in a thick oil which was takenup in IPAc (250 mL) then washed with water (3×250 mL). The organic phasewas dried over sodium sulfate (Na₂SO₄), filtered and concentrated underreduced pressure to provide the title compound (15.1 g, 60%) as a whitesolid.

¹H NMR (500 MHz, d₆-DMSO) 7.87 (s, 1H), 5.97 (d, J=6.0, 1H), 4.02 (dt,J=6.0, 3.8 Hz, 1H), 2.70-2.65 (m, 1H), 1.60-1.20 (m, 4H), 0.88 (t, J=7.0Hz, 3H), 0.63-0.58 (m, 2H), 0.51-0.46 (m, 2H).

Example 9 3-Amino-N-cyclopropyl-2-hydroxyhexanamide

The azide of Example 7 (15.1 g, 71.3 mmol), Pd/C (1.5 g, 5 wt %, 50%wet) and MeOH (150 mL) was charged to a pressure vessel then purged withnitrogen gas for 5 min. The vessel was sealed, pressurized to 1 bar withnitrogen gas then released three times. The same was repeated withhydrogen gas. After the third purge with hydrogen the vessel was chargedwith 3 bar of hydrogen. Agitation was begun and a temperature of 25±5°C. was maintained. Reaction was stirred in this manner for 14 hoursafter which time the reaction mixture was filtered through a pad ofCelite 545 and the solvent removed to provide crude amino-alcohol (8.48g) as a yellow solid. To this material was added acetonitrile (ACN; 150mL) and the reaction heated to reflux at which time all of the solidsdissolved. The mixture was then cooled to 25±5° C. and the white needlesformed were collected, washed with cold ACN and dried to providepurified amino-alcohol (4.87 g).

¹H NMR (500 MHz, d₆-DMSO): 8.05 (br s, 3H), 4.20 (d, J=3.2, 1H),3.42-3.34 (m, 1H), 2.71-2.65 (m, 1H), 1.51-1.20 (m, 4H), 1.17 (d, J=6.5Hz, 1H), 0.83 (t, J=7.6 Hz, 3H), 0.64-0.60 (m, 2H), 0.54-0.49 (m, 2H).

Example 10 3-Amino-N-cyclopropyl-2-hydroxyhexanamide, L-tartaric acidsalt

To a racemic mixture of 3-amino-N-cyclopropyl-2-hydroxyhexanamide (100mg, 0.53 mmol) in MeOH (1 mL) was added L-tartaric acid (39.7 mg, 0.26mmol) in MeOH (20 μL) and the mixture cooled to 0±5° C. After 48 h at0±5° C. a white precipitate had formed which was collected, washed withmethyl tert-butyl ether (2×5 mL) then dried to provide the titlecompound. Chiral HPLC analysis and comparison with an authentic sampleof the chiral amino-alcohol hydrochloride salt showed that the titlecompound was obtained with 62 ee %.

Example 11 3-Amino-N-cyclopropyl-2-hydroxyhexanamide, deoxycholic acidsalt

To a three-neck 250 mL round bottom flask equipped with mechanicalstirrer and containing the racemic3-amino-N-cyclopropyl-2-hydroxyhexanamide (10.0 g, 53.69 mmole) in THF(100 mL) was charged deoxycholic acid (15.8 g, 40 27 mmole, 0.75 eq.).The reaction mixture was stirred and heated at 65±5° C. for 2 hours. Theresulting homogeneous mixture was allowed to cool to temperaturesbetween 22 and 25° C. over an hour, and it was maintained at the sametemperature range for 4 hours. The precipitated solids were collected byfiltration, washed with THF (10 mL), dried overnight to give 12.2 g ofthe deoxycholic acid salt of 3-amino-N-cyclopropyl-2-hydroxyhexanamide(41%, Enatiomeric Ratio(ER)=3:97) as a white solid.

Example 12 3-Amino-N-cyclopropyl-2-hydroxyhexanamide, hydrochloric acidsalt

To a three-neck 250 mL round bottom flask equipped with mechanicalstirrer and containing the mixture of the deoxycholic salt obtained inExample 11 in 2-propanol (62 mL) was added 5 to 6 N HCl solution inisopropyl alcohol (66 mL, 3 eq.) with stirring. The resulting solutionwas heated at 75±5° C. for an hour and allowed to cool to temperaturesbetween 22 and 25° C. over 1 hour, and it was maintained at the sametemperature range for 2 hours. The precipitated solids were collected byfiltration, washed with 2-propanol (12 mL, 1 v), dried overnight to give7.2 g of 3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloric acidsalt (75%, Enatiomeric Ratio(ER)=0.05:99.95) as a white solid.

Example 13 Preparation of(1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N—((S)-1-(cyclopropylamino)-1,2-dioxo-hexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide

Step a: Preparation of (Compound vii Shown Below)

The sultam shown above vi is prepared by known methods such as thosedescribed in Y. Elemes and U. Ragnarsson, J. of Chem. Soc., Perkin 1,1996, 6, p. 537; W. Oppolzer, et. al., Helv. Chim. Acta., 1994, 25:2363), by using the corresponding unsubstituted sultam and propyliodide.

A 500 mL round-bottomed-flask with a magnetic stir bar and N₂ inlet ischarged with vi (17.32 g, 45.8 mmol), and THF (229 mL). The resultingsolution is cooled to −78° C. and n-BuLi (31.5 mL of a 1.6 M solution inhexane, 50.3 mmol) is added via syringe pump over 1 hour. The resultingyellow solution is aged for 30 minutes and then a solution of HPMA (56mL) and n-PrI (13.4 mL, 137 mmol) is added over 30 minutes. The mixtureis allowed to warm to the room temperature over 8 hours. The mixture iscooled to −20° C. and H₂O (50 mL) is added. The reaction is extractedwith EtOAc (400 mL) and the organic phases are dried over MgSO₄ andconcentrated to provide 61.3 g of the crude oil. Chromatography on 500 gof silica gel eluting with 2:1 heptane/EtOAc followed by concentrationof the rich cut give 20.35 g of a white solid. This is recrystallizedfrom EtOH (210 mL) to give compound vii as a white crystalline solid.

Step b: Preparation of (S)-2-(benzyloxycarbonylamino)-Pentanoic Acid(Compound viii Shown Above)

Compound vii (15.39 g, 32.1 mmol) is combined with THF (100 mL) and 1NHCl (50 mL). The resulting emulsion is stirred overnight at the roomtemperature and then concentrated under reduced vacuum to provide athick oil. The oil is dissolved in THF (100 mL), water (25 mL) and LiOH(3.08 g, 128 mmol) is added. The resultant solution is stirred overnightat the room temperature and then concentrated to remove the THF,resulting a hazy light yellow emulsion. The emulsion is diluted withwater (25 mL) and extracted with CH₂Cl₂ (3×50 mL). The aqueous phase isdiluted with THF (200 mL) and then cooled to 0° C. while stirringrapidly and CBZ-Cl (7.6 mL, 54 mmol) is added dropwise over 15 minutes.After 1 hour at 0° C., the THF is removed in vacuo and the residue isacidified by addition of 50 mL of 1 N HCl. This is extracted with EtOAc(3×100 mL) and the organic phase is dried over Na₂SO₄ and concentratedto provide an oil. The residue is dissolved in EtOAc (25 mL) and heptane(150 mL), seeded and stirred overnight at the room temperature. Thesolids are collected on a frit, rinsed with heptane (30 mL) and airdried to give compound viii.Step c: Preparation of (S)-2-(benzyloxycarbonylamino)-Pentanoic Acid

As shown below, the title compound is prepared by hydrolysis of thesultam product of Step a and conversion of the resultant free amino acidto its Cbz derivative by known methods (see, e.g., W. Green, P. G. M.Wuts, Protective Groups in Organic Synthesis, Wiley-Interscience, NewYork, 1999).

Step d: Preparation of (S)-benzyl1-(methoxy(methyl)amino)-1-oxo-2-pentan-2-ylcarbamate

To a flask containing 1.0 g of (S)-2-(benzyloxycarbonylamino)-pentanoicacid (3.97 mmol) in 20 mL of dichloromethane maintained at 0° C., isadded 3.0 eq. of N-methylmorpholine (700 uL), 1.5 eq. ofN,O-dimethylhydroxylamine hydrochloride (581 mg) and 1.5 eq. of EDCI(1.14 g). The reaction mixture is stirred overnight from 0° C. to theroom temperature. The reaction mixture is then diluted indichloromethane and washed with HCl (1N) and brine. The organic layer isdried over MgSO₄. The crude mixture is purified by flash chromatography(ethyl acetate 15-75% in hexanes) to afford the title compound.Step e: Preparation of (S)-benzyl 1-oxo-2-pentan-2-ylcarbamate

Using procedures described in WO 02/18369, the Cbz-protected amino acidof Step d is converted to the title compound. Specifically, into a flaskcontaining 1.0 eq. of (S)-benzyl1-(methoxy(methyl)amino)-1-oxo-2-pentan-2-ylcarbamate (810 mg, 2.75mmol) in 10 mL of dry THF maintained at 0° C. (in an ice bath) is addedslowly 1.7 eq. of a solution of lithium borohydride (1.0M) (4.67 mL).After about 10 minutes, the ice bath is removed and the reactioncontinue for an hour. The reaction solution is quenched at 0° C. byadding 5 mL of a solution of KHSO₄ (10%). The solution is then dilutedby the addition of 10 mL of HCl (1N). The mixture is stirred for 30minutes, then extracted 3 times with dichloromethane. The organic phasesare combined and washed with a solution of HCl (1 N), water and brine.The organic phase is then dried over MgSO₄ and the volatile evaporates.The aldehyde is used as is in the next step.Step f: Preparation of benzyl(3S)-1-(cyclopropylamino)-2-hydroxy-1-oxo-hexan-3-ylcarbamate.

Cyclopropyl isocyanide is prepared according to the scheme shown below.

Specifically, the cyclopropyl isonitrile is coupled with the aldehydeproduct of Step d to give the title compound as described in J. E.Semple et al., Org. Lett., 2000, 2(18), 2769; Lumma W., J. Org. Chem.,1981, 46, 3668.Step g: Preparation of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide

Hydrogenolysis of the Cbz compound of Step e is achieved by using apalladium on carbon catalyst in the presence of hydrogen to give thetitle compound. Shown in the following schemes are Steps d, e, f, and g.

Step h: Preparation of(1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((35)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide

The title compound is prepared from the hydroxy-amino amide product ofStep g by condensation with the appropriate acid in the presence of acoupling reagent such as, e.g., EDCI and HOSu. Specifically, in a flaskcontaining 1.2 eq. of(1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)octahydrocyclopenta[c]pyrrole-1-carboxylicacid (1.59 g) in 20 mL of DMF, is added 2.5 eq. of diisopropylamine (980uL), 1.2 eq. N-hydroxybenzotriazole hydrate (411 mg) and 1.3 eq. of EDCI(558 mg). After 15 minutes of stirring at the room temperature, 1.0 eq.of (3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride (500 mg)is added to the mixture. After another 24 hours, the reaction mixture isdiluted into 400 mL of ethyl acetate. The organic phase of the mixtureis washed with HCl (1N), water, saturated sodium bicarbonate solution,brine, and then dried over MgSO₄. The crude product is purified bychromatography on silica (ethyl acetate 70-100% in Hexanes) to give thetile compound.Step i: Preparation of(1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N—((S)-1-(cyclopropylamino)-1,2-dioxo-hexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamide

The title compound is prepared by oxidation of the product of Step hwith a suitable oxidizing reagent such as Dess-Martin periodinane orTEMPO and sodium hypochlorite. Specifically, in a flask containing 1.31g of(1S,3aR,6aS)-2-((S)-2-((S)-2-cyclohexyl-2-(pyrazine-2-carboxamido)acetamido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)octahydrocyclopenta[c]pyrrole-1-carboxamidein 40 mL of dichloromethane is added at room temperature 1.06 g ofDess-Martin periodinane. After 2 hours of stirring, 50 mL of sodiumbisulfite (1N) is added, and the mixture is stirred for 30 minutes. The2 phases are separated, the organic is washed with water twice, brineand dried over Na₂SO₄. The crude product was purified by chromatographyon silica (ethyl acetate 20-100% in Hexanes) to give the title compound.The diastereoisome ratio is determined by chiral HPLC normal phase.

The following scheme shows the reactions of both Steps g and h.

Example 14 Preparation of(2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride

Step 1. Reduction (trans-2-Hexen-1-ol)

To a three-neck 250 mL round bottom flask equipped with mechanicalstirrer and reflux condenser is charged 2-hexyn-1-ol (10 g, 0.1 mole)and THF (100 mL, 10 vol). The resulting mixture is cooled down to 0±5°C. and then Red-Al (65% in Toluene, 32 mL, 1.6 eq) is added slowly undera nitrogen atmosphere between 0° C. and 20° C. The resulting mixture isallowed to warm to 25° C. and stirred for 5 hours. The reaction mixtureis then cooled to −5±5° C. and H₂O (8.2 g, 4 eq) is added dropwisebetween 0° C. and 15° C. To the resulting mixture is charged IPAC (50mL, 5 vol) and saturated NH₄Cl solution (50 mL, 5 vol). After stirringthe mixture for 10 minutes, the white solid formed is filtered out. Theorganic layer from the filtrate is separated and the aqueous layerextracted with IPAC (30 mL, 3 vol). The organic layers are combined andwashed with water (30 mL, 3 vol) and dried over MgSO₄ and concentratedto afford the product, i.e., compound 2. The crude product is used forthe next step without further purification.

Step 2. Oxidation: MnO₂ (trans-2-Hexen-1-al)

To a three-neck 250 mL round bottom flask equipped with mechanicalstirrer containing 2-Hexen-1-ol-3d (10 g, 0.1 mole) in CH₂Cl₂ (150 mL,15 vol) is charged activated MnO₂ (87 g, 10 eq) at the room temperature.After vigorous stirring for 1 hour, another portion of MnO₂ (16 g, 2 eq)is added and the shaking is continued for 4 hours. The reaction solutionis filtered through a pad of Celite®. The solvent is removed under vacuo(25° C., 100 mmHg) to give the crude aldehyde product (i.e., compound3). The crude product is used for the next step without furtherpurification.

Step 3. Oxidation: NaClO₂ (trans-2-Hexenoic acid)

To a three-neck 500 mL round bottom flask equipped with mechanicalstirrer and reflux condenser is charged 2-hexen-1-al-3d (10 g, 0.1mole), tert-BuOH (90 mL, 9 vol), and 2-methyl-2-butene (30 mL, 3 vol).The resulting solution is added with a freshly prepared aqueous NaClO₂(27.4 g, 3 eq) and NaH₂PO₄ (62.9 g, 4 eq) in water (200 mL) over 30minutes. The reaction mixture is stirred at room temperature for 2hours. The reaction solution is cooled to 0° C. and was added withsaturated Na₂SO₃ aqueous solution until the reaction color becomescolorless. The stirring is stopped and the organic layer is separatedand the aqueous layer is extracted with EtOAc (3 vol×3). The organiclayers are combined and concentrated in vacuo until the total volumebecomes 3 vol. The resulting solution was extracted with 1 N NaOH (3vol×3) and the remaining organic layer was discarded. The combinedaqueous solution was acidified with 6 N HCl until the pH became 1.0. Thesolution is extracted with CH₂Cl₂ (3 vol×5). The combined organic layerare dried over MgSO₄ and concentrated to get the product (i.e., compound4).

Step 4. Amidation ((E)-N-cyclopropylhex-2-enamide)

To a three-neck 250 mL round bottom flask equipped with mechanicalstirrer and reflux condenser is charged 2-hexenoic acid-3d (10 g, 0.09mole), IBCF (13 g, 1.1 eq) in CH₂Cl₂ (100 mL, 10 vol). The resultingsolution is cooled to 0° C. and NMM (13.2 g, 1.5 eq) was added slowly bycontrolling the temperature between 0 and 20° C. Then, the mixture isallowed to warm to room temperature and stirred for 1 hour. To theresulting solution is added cyclopropyl amine (5.9 g, 1.2 eq) and thesolution stirred for 2 hours. The reaction mixture is washed with 1 NNaOH (3 vol×2), 1N HCl (3 vol×2), and brine solution (3 vol), and water(3 vol). The organic layer is dried over MgSO₄ and concentrated toafford the crude product as oil. The crude product is dissolved withheptane (5 vol) and cooled to −78° C. with stirring. The precipitatedsolid is filtered and dried to give the product (i.e., compound 5).

Step 5. Epoxidation (N-cyclopropyl-3-propyloxirane-2-carboxamide)

To a three-neck 250 mL round bottom flask equipped with mechanicalstirrer and containing (E)-N-cyclopropylhex-2-enamide-3d 5 (10 g, 0.06mole), urea hydrogen peroxide (25 g, 4 eq), and p-TsOH (12.3 g, 1 eq) inCH₂Cl₂ (100 mL, 10 vol) at 0° C. is added trifluoroacetic anhydride(40.9 g, 3 eq) in CH₂Cl₂ (50 mL, 5 vol) over 30 minutes. The reactionmixture is heated to 40±5° C. and stirred for 3 hours. After cooling to0° C., the reaction is quenched by adding 6 N NaOH (100 mL, 10 vol)slowly and stirring for 30 minutes. The organic layer is separated,washed with brine (5 vol) and water (5 vol). The resulting organic layeris dried over MgSO₄ and solvent evaporated to afford the epoxide product(i.e., compound 6), which is used for the next step without furtherpurification.

Step 6. Azide Formation (3-azido-N-cyclopropyl-2-hydroxyhexanamide)

To a three necked 250 mL round bottom flask equipped with mechanicalstirrer and reflux condenser containing the epoxide-3d 6 (10 g, 0.06mole) and anhydrous magnesium sulfate (14.1 g, 2.0 eq) in MeOH (100 mL,10 vol) is added sodium azide (15.3 g, 4.0 eq) in one portion. Theresulting mixture is heated to 65±5° C. and stirred for 5 hours. Thereaction solution is cooled to the room temperature and IPAC (100 mL, 10vol) is added and stirred for 10 minutes. The mixture is filteredthrough a pad of Celite® to remove insoluble salts and the resultingclear solution is concentrated to 3 vol. To the resulting solution isadded IPAC (170 mL, 17 vol) and the mixture is stirred for 10 minutes.Again, the solution is filtered through a pad of Celite® to afford theproduct, the azide-3d (i.e., compound 7) as a solution in IPAC (about200 mL) for the next step without further purification.

Step 7. Hydrogenation (Racemic Warhead)

To a 500 mL of autoclave hydrogenation reactor equipped with mechanicalstirrer containing the azide-3d (i.e., compound 7) (200 mL, 0.05 mole)in IPAC obtained in the previous step in a hydrogenation reactor ischarged Pd/C (10% Pd, water 50%, 0.8 g). The solution is charged withnitrogen (1.0 atm) and released three times and then charged withhydrogen (3.0 atm) and released three times. The resulting solution ischarged with hydrogen (3 atm) and stirred for 5 hours. After releasingthe hydrogen gas, the solution is purged with nitrogen for 5 minutes. Tothe resulting solution was added MeOH (30 ml, 3 vol) and the reactionmixture is heated to 50±5° C. The reaction mixture is filtered through apad of Celite® to afford a clear solution. The product is isolated byconcentrating the solution at 20±5° C. until 3 vol of the solutionremains. The solid is collected by filtration, washed (IPAC, 3 vol), anddried to give the product (i.e., compound 8).

Step 8. Resolution of 3-amino-N-cyclopropyl-2-hydroxyhexanamide

I. Salt formation

To a three-neck 250 mL round bottom flask equipped with mechanicalstirrer and containing the racemic3-amino-N-cyclopropyl-2-hydroxyhexanamide (10 g, 0.05 mole) in THF (100mL, 10 v) is charged deoxycholic acid (15.7 g, 0.75 eq.). The reactionmixture is heated to 65±5° C. and stirred for 1 hour at the temperature.The resulting homogeneous mixture was cool down to 23±2° C. over 1 hour,and it was maintained at the same temperature range for 1 hour. Theprecipitated solids were collected by filtration, washed with THF (50mL, 5 vol), dried to give a salt.

To a three-neck 250 mL round bottom flask equipped with mechanicalstirrer is charged the salt (obtained in previous step) and 2-propanol(62 mL, 5 vol). The solution is heated to 75±5° C. and 5 to 6 N HClsolution in IPA (12 mL, 3 eq.) is added slowly with vigorous stirring.The resulting solution is stirred at the same temperature for 1 hour andcooled to 23±2° C. The reaction mixture is maintained at the sametemperature for 1 hour. The precipitated solids are collected byfiltration, washed with 2-propanol (36 mL, 3 vol), dried to give(2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide hydrochloride(Enatiomeric Ratio=0:100).

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the following claims. Otheraspects, advantages, and modification are within the scope of thefollowing claims.

1. A process for preparing an optically enriched compound of Formula 1

wherein: the carbon atoms alpha and beta to the carboxy group are stereocenters; R₁ and R′₁ are each independently H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic; R′₂ is —NHR₂ or —OE; R₂ is H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic; and E is C₁-C₆ alkyl or benzyl; comprising the steps of: a) forming a salt of a compound of Formula 1 b) crystallizing said salt to give a compound of greater than 55% enantiomeric excess.
 2. The process of claim 1, wherein R₁ is C₁-C₆ alkyl, R′₁ is H and R′₂ is —NHR₂ wherein R₂ is C₁-C₆ alkyl or C₁-C₆ cycloalkyl.
 3. The process of claim 2, wherein R₁ is propyl and R₂ is cyclopropyl.
 4. The process of claim 1, further comprising aminating a compound of Formula ii

with an aminating reagent to provide a compound of Formula iii


5. The process of claim 4, wherein the aminating reagent is an azide salt and the intermediate azido compound is reduced by hydrogenation.
 6. The process of claim 4, further comprising oxidizing an unsaturated compound of Formula i

wherein R₁₂ is —NHR₂ or —OE, wherein E is C₁-C₅ alkyl or optionally substituted benzyl, with an oxidizing reagent to provide a compound of Formula ii.


7. The process of claim 6, wherein the oxidizing reagent is t-butyl hydroperoxide.
 8. The process of claim 6, wherein the oxidizing reagent includes a chiral reagent.
 9. The process of claim 8, wherein the oxidizing reagent is a mixture of samarium (III) isopropoxide, triphenyl arsine oxide, S-(−)1,1′-bi-2-naphthol and 4 Å molecular sieves.
 10. The process of claim 6, wherein the oxidizing reagent is urea-hydrogen peroxide in the presence of trifluoroacetic anhydride.
 11. The process of claim 6, wherein R′₂ is —OE.
 12. The process of claim 6, wherein R′₂ is —NHR₂.
 13. The process of claim 11, further comprising hydrolyzing the compound of Formula ii to give an acid and then converting the acid to an amide compound of Formula ii wherein R′₂ is —NHR₂.
 14. A process for preparing a compound of Formula 1

wherein: R₁ and R′₁ are each independently H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic; R₂ is H, optionally substituted aliphatic, optionally substituted cycloaliphatic, optionally substituted arylaliphatic, optionally substituted heteroaliphatic or optionally substituted heteroarylaliphatic; and the compound of Formula 1 has an enantiomeric excess of greater than 55%, comprising the steps of: a) oxidation of an unsaturated compound of Formula i

to provide a compound of formula ii

b) reacting a compound of Formula ii with an aminating reagent to provide a compound of Formula iii

c) forming a salt of a compound of Formula iii with an optically active organic acid; d) crystallizing said salt to give a compound of greater than 55% enantiomeric excess.
 15. The process of claim 14, wherein the compound of Formula 1 is (2S,3S)-3-amino-N-cyclopropyl-2-hydroxyhexanamide.
 16. The process of claim 14, wherein the organic acid is L-tartaric acid.
 17. The process of claim 14, wherein the organic acid is deoxycholic acid.
 18. A compound which is N-cyclopropyl-3-propyloxirane-2-carboxamide.
 19. A compound which is N-cyclopropyl-3-propyloxirane-2-carboxamide.
 20. A compound which is 3-azido-N-cyclopropyl-2-hydroxyhexanamide.
 21. A compound which is 3-amino-N-cyclopropyl-2-hydroxyhexanamide, L-tartaric acid salt.
 22. A compound which is 3-amino-N-cyclopropyl-2-hydroxyhexanamide, deoxycholic acid salt. 